How did a vaccine enhance HIV acquisition

疫苗如何促进艾滋病毒感染

• 批准号: 8924774
• 负责人: CHRISTOPHER James MILLER
• 金额: $ 71.35万
• 依托单位: UNIVERSITY OF CALIFORNIA AT DAVIS
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-06-15 至 2020-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8924774
• 关键词: Acquired Immunodeficiency Syndrome; Adenoviruses; Animal Model; Animals; Antigens; Antiviral Agents; Biological Markers; Blood; CD4 Positive T Lymphocytes; CD8B1 gene; Cells; Dose; Enrollment; Epithelial Cells; Equilibrium; Futility; Gagging; Goals; HIV; HIV Antigens; HIV Envelope Protein gp120; HIV Infections; HIV Vaccine Trials Network; HIV vaccine; HIV-1; Heterosexuals; Homing; Human; Immune; Immune response; Immunity; Immunization; Infection; Irrigation; Macaca mulatta; Mediating; Modeling; Monkeys; Participant; Placebos; Population; Predisposition; Proteome; Recombinants; Risk; Role; SIV; SIV Vaccines; Sampling; Serotyping; Signal Transduction; Subgroup; T cell response; T-Cell Activation; T-Lymphocyte; Testing; Time; Tissues; Vaccinated; Vaccination; Vaccines; Viral Load result; Virus; efficacy trial; env Gene Products; follow-up; male; meetings; men; men who have sex with men; nonhuman primate; pandemic disease; penis foreskin; plasmid DNA; prevent; public health relevance; research study; seropositive; transmission process; vaccine candidate; vector

 DESCRIPTION (provided by applicant): To date, six human efficacy trials of candidate HIV vaccines have been completed. These trials have evaluated four different vaccine strategies have been completed. In the RV144 Thai trial a canarypox prime followed by boosts with canarypox and gp120 envelope protein were evaluated. Rv144 is the only trial to demonstrate that a vaccine candidate can protect against HIV acquisition, although protection was modest. The other trials failed to demonstrate any protection against HIV acquisition. Further, in the STEP and Phambili trials more people receiving the vaccine than the placebo became infected, demonstrating that the HIV vaccines have the potential to enhance susceptibility to HIV infection. Similarly, rhesus macaques chronically infected with Ad5 and then immunized with a replication defective Ad5 SIVmac239 Gag-Pol-Nef vaccine were more susceptible to penile SIV infection than unimmunized rhesus macaques. We will use this animal model to understand how an HIV vaccine enhanced HIV acquisition. In particular we will determine 1) if Ad5 persistence in tissues of the foreskin leads to increased T cell recruitment to, and retention in, that is amplifid by 3 Ad5 vector immunizations; 2) if Ad5 infected RM have increased numbers of activated CD4+ T cells/TH17 cells in the foreskin after immunization compared to Ad5- RM; 3) ifAd5 infected RM have more Ad5 specific CD4+ T cells and SIV-specific CD4+ T cells in the foreskin after immunization compared to Ad5- RM; 4) if Ad5 infected RM have more innate immune signals emanating from epithelial cells, DC and others in the foreskin that drive T cell recruitment and survival after immunization compared to Ad5- RM. Understanding the underlying mechanisms behind the vaccine-enhanced HIV susceptibility in the STEP trail will allow the field to avoid testing harmful HIV vaccines in people.

 描述（由申请人提供）：迄今为止，已完成六项候选HIV疫苗的人体有效性试验。这些试验评估了四种不同的疫苗策略已经完成。在RV 144泰国试验中，评估了金丝雀痘初免，然后用金丝雀痘和gp 120包膜蛋白加强。Rv 144是唯一一个证明候选疫苗可以预防艾滋病毒感染的试验，尽管保护作用不大。其他试验未能证明对艾滋病毒感染有任何保护作用。此外，在STEP和Phambili试验中，接受疫苗的人比安慰剂感染的人更多，这表明HIV疫苗有可能增强对HIV感染的易感性。类似地，用Ad 5慢性感染然后用复制缺陷型Ad 5 SIVmac 239 Gag-Pol-Nef疫苗免疫的恒河猴比未免疫的恒河猴更容易感染阴茎SIV。我们将使用这种动物模型来了解HIV疫苗如何增强HIV感染。特别地，我们将确定1）Ad 5在包皮组织中的持续存在是否导致增加的T细胞募集和保留，即通过3次Ad 5载体免疫接种来抑制; 2）与Ad 5- RM相比，Ad 5感染的RM在免疫接种后是否具有增加的包皮中活化的CD 4 + T细胞/TH 17细胞的数量;（3）Ad 5感染的RM在免疫后包皮中有更多的Ad 5特异性CD 4 + T细胞和SIV特异性CD 4 + T细胞; 4）如果Ad 5感染的RM具有更多的从上皮细胞发出的先天免疫信号，与Ad 5- RM相比，包皮中的DC和其他细胞在免疫后驱动T细胞募集和存活。了解STEP试验中疫苗增强HIV易感性背后的潜在机制将使该领域避免在人体中测试有害的HIV疫苗。